PROJECT SUMMARY: Relapsing-remitting multiple sclerosis (RRMS) is a debilitating disorder of the central nervous system (CNS) that affects over 400,000 U.S. citizens and millions worldwide. RRMS is the most common non-traumatic cause of neurologic disability in young adults, with disease onset typically occurring between 20 and 30 years of age. There is no cure for RRMS, and current therapeutic strategies carry significant risk. RRMS patients develop inflammatory lesions in their brain and spinal cord characterized by massive immune cell infiltration. This process results in the destruction of myelin, a fatty sheath that encompasses neuronal axons and is important for their health and function. In addition to this demyelination, axonal damage, neuronal loss, and tissue scarring are also classic features of RRMS. These hallmarks of disease are responsible for the neurologic deficits experienced by RRMS patients, and are incited by immune cell inflammatory activity in the brain. Myeloid cells (MC), a branch of the immune system, are known drivers of this devastating pathologic process. MC dominate the RRMS lesion and the extent of irreversible neurologic damage present is most strongly influenced by MC abundance. In vitro studies suggest that MC support inflammatory programs by increasing their metabolism of glucose, thus generating excitement about the therapeutic potential of targeting MC metabolic pathways to treat inflammatory diseases. However, this enthusiasm is tempered by the following considerations: metabolic characteristics of MC during demyelinating diseases like RRMS have yet to be elucidated, and systemic administration of metabolic inhibitors for chronic indications is unattractive. The first aim of this project is to establish the metabolic characteristics of individual MC subsets found in the demyelinating CNS. This goal is founded in preliminary data demonstrating that bulk MCs isolated directly from the demyelinating CNS upregulate glyclolytic machinery, including alternative isoforms of glycolytic enzymes that are not otherwise expressed in normal tissues. The engagement of this glycolytic profile is associated with a robust increase in inflammatory gene signature, and drugs that block these induced enzymes potently restrict the inflammatory responses of these immune cells in ex vivo systems. The second aim of this project is to pharmacologically and genetically target an isoform of a glycolytic enzyme induced during immune cell activation to treat CNS demyelination. Collectively, the results of these studies will provide significant conceptual advancements in the understanding of RRMS disease mechanisms, and may pave the way for the development of novel therapeutics to manage this debilitating disease.